A major difficulty in developing a HIV vaccine has been in identifying a vaccine approach that is effective against a broad range of HIV strains including field isolates from different subtypes or clades. A number of animal models for AIDS, including feline immunodeficiency virus (FIV) infection of cats, have been used to test different vaccine approaches. We have used FIV model to identify vaccine strategies for HIV. Our findings from FIV vaccine studies suggest that both humoral and cellular immunities against the virus may be required to get full protection against heterologous strains. Similarly, evaluation of HIV infection in humans suggest that both strong anti-HIV humoral and cellular immunities are necessary to delay the onset of disease. Further, we have demonstrated that inactivated FIV and infected-cell vaccines can protect cats against challenge infection with homologous and slightly heterologous strains but not against strains from different subtypes. Based on these findings, we propose that a broad-spectrum vaccine for AIDS viruses can be generated by combining prototype virus isolates from different subtypes. Such a combination should elicit a broad-range of protective immunity against FIV. We propose to test this hypothesis by developing inactivated multi-subtype FIV vaccine consisting of prototype strains from three subtypes (A, B, D) and test its protective efficacy in cats. Vaccinated cats will be monitored for humoral (VN antibodies) and cellular (CTL) responses before and after challenge with homologous and heterologous strains. Sera and immunocytes from cats will be tested in vitro for VN and CTL activities, respectively against homologous and heterologous strains, thereby determining if such vaccines can elicit broad-range protection. The type(s) of immunity required for protection will be determined by performing both adoptive transfer and passive immunization studies. Adoptive transfer studies will be performed using immune cells (enriched CD4+ T cell, CD8+ T cell, B cell, and monocyte populations) from vaccinated cats. Antiviral antibodies from Immune serum of vaccinated cats will be purified and administered to naive cats. In the development of an efficacious FIV vaccine, it will be necessary to demonstrate that the vaccination does not induce vaccine resistant variants. Thus, multi-subtype vaccine will be evaluated for development of vaccine-induced variants.